Study On The Construction Of Nanotheranostic Agents Based On Rare Earth-Doped Prussian Blue For Diagnosis And Treatment Intergration Of Breast Cancer

At present,breast cancer has become the most common cancer in the world.It has a rapid growth trend and has seriously threatened women's health.Early diagnosis and treatment are of great significance to improve the survival rate of breast cancer patients.Nanomaterials are widely used in the preparation of biomedical materials due to their versatility.Designing nanotheranostic agents with diagnostic and therapeutic functions is an effective method to improve cancer treatment.Prussian blue nanaparticles(PB)are widely used in the treatment of cancer due to high biological safety,good photothermal performance and imaging function.However,there are some limitations of PB as nanotheranostic agents,,such as unregulated photothermal performance and low catalytic efficiency in tumor microenvironment.Based on this,rare earth-doped Prussian blue nanotheranostic agents are designed for treatment of breast cancer,and the performance of Prussian blue was optimized based on the structure-activity relationship to realize the integration of diagnosis and treatment of breast cancer.The work of this paper is mainly developed from the following aspects:In the first chapter,kinds of cancer diagnosis methods were introduced,including tumor marker detection,genetic detection,X-ray and CT detection,magnetic resonance imaging and fluorescence imaging,and the application characteristics and limitations of each method were described.Then the advantages and disadvantages of several common cancer treatment methods weret compared,the shortcomings of single modality treatment methods and the purpose and significance of developing multifunctional nano-diagnostic and therapeutic agents were analyzed.Finally,the research purpose of this thesis,the synthetic ideas of nanotheranostic agents and the expected diagnosis and treatment effects were clarified,In the second chapter,by adjusting the ratio of Gd³⁺and Tm³⁺doping,a series of dual rare earth doped Prussian blue nanoparticles(PB)were synthesized,and the rare earth doped nanoparticles Gd/Tm-PB with the best morphology,strongest photothermal performance,and best fluorescence were selected.Then the imidazole metal-organic framework ZIF-8 with acid response function was wrapped on the surface of Gd/Tm-PB,and then the surface was modified with polydopamine(PDA)to form the composite nanomaterial Gd/Tm-PB@ZIF-8/PDA.The morphology and structure were proved by SEM,TEM,XRD,FTIR and other characterization methods.The ability of Gd/Tm-PB@ZIF-8/PDA multimodal imaging was verified by measuring T₁/T₂magnetic resonance imaging(T₁/T₂-MRI)and fluorescence imaging(FOI).The photothermal performance of Gd/Tm-PB@ZIF-8/PDA under 808nm excitation conditions was explored,and the excellent photothermal conversion ability was confirmed.Doxorubicin hydrochloride(DOX)was used as a drug model,and the release experiment under different p H and different concentrations of glutathione(GSH)confirmed the p H/GSH dual response release function.Cytotoxicity experiments and mouse experiments proved the synergistic effect of chemotherapy/photothermal therapy on breast cancer cells.Experimental results proved that Gd/Tm-PB@ZIF-8/PDA is a multi-functional nano-diagnostic and therapeutic agent that integrates multi-modal imaging,p H/GSH dual-response drug release and excellent photothermal performance.In the third chapter,aiming at the potential catalytic therapy performance of rare earth doped Prussian blue,it was proposed to synthesize rare earth doed Prussian blue that integrate chemotherapy/photothermal therapy/catalytic therapy.Three kinds of Prussian blue nanoparticles doped with rare earth ions,Yb³⁺,Gd³⁺,and Tm³⁺,were synthesized by co-precipitation method,and the photothermal and catalytic performances of Prussian blue nanoparticles doped with different rare earth ions were compared,and the optimal photothermal performance was screened out.Prussian blue Yb-PB doped with rare earth ions and catalytic properties.Its structure was confirmed by XRD,FTIR,and EDX.Then,PDA with certain GSH scavenging ability was wrapped on the surface of Yb-PB,and composite nano-material Yb-PB@PDA was obtained.Through a series of characterization methods,the photothermal conversion efficiency and photothermal stability were studied,and the infrared thermal imaging function was confirmed.The Methylene blue(MB)catalytic degradation experiment proved the excellent catalytic performance of Yb-PB@PDA,and it can generate hydroxyl radicals(·OH)under the condition of high glutathione concentration.Experiments verified that near-infrared laser irradiation can produce more·OH,indicating that the higher catalytic efficiency of Yb-PB@PDA in the tumor microenvironment.The dual response of p H/GSH release function was proved through the release experiment in the conditions of different p H and different concentration of glutathione(GSH).It was found more drugs can be releases with the irradiation of 808nm near-infrared laser,which is expected to kill more Cancer cells.Therefore,Yb-PB@PDA is a nanotheranostic agent integrating diagnosis and photothermal therapy/chemodynamic therapy/chemotherapy.